Methods of treating or preventing interstitial cystitis

ABSTRACT

PCT No. PCT/US97/03410 Sec. 371 Date Sep. 8, 1998 Sec. 102(e) Date Sep. 8, 1998 PCT Filed Mar. 7, 1997 PCT Pub. No. WO97/33880 PCT Pub. Date Sep. 18, 1997This invention provides methods for the treatment or prevention of interstitial cystitis or urethral syndrome in a mammal which comprise administering to a mammal in need thereof an effective amount of duloxetine.

This case is a 371 of PCT/USA97/03410 filed Mar. 7, 1997.

BACKGROUND OF THE INVENTION

Interstitial cystitis is a chronic debilitating inflammatory disorder ofthe bladder. The disease is most common in women ranging in age fromabout thirty to sixty with onset of the condition typically occurring atabout forty years of age. It is characterized by a number of urinarydifficulties, such as suprapubic pressure and pain, with bladderfilling, urinary frequency, nocturia, dysuria, urgency adn irritativevoiding associated with morphological and histological changes in thebladder. The condition is characterized as "interstitial cystitis"because it is believed the condition does not affect the surface of thebladder, but instead involves the spaces between the cells, namely theinterstices, in the lining of the bladder.

Urethral syndrome is a related painful voiding disorder of unknownetiology affecting women exhibiting many of the conditions set forthabove.

As noted in U.S. Pat. No. 5,145,859, issued Sep. 8, 1992, the entirecontents of which are herein incorporated by reference, there are anumber of compounds proposed to treat these conditions, based ondiffering theories as to the etiology of interstitial cystitis andurethral syndrome. None of these treatment regimens has provencompletely successful to date.

Because of the current dissatisfaction of the currently marketedtreatments for interstitial cystitis within the affected population,there exists a need for a more efficacious and safe treatment.

SUMMARY OF THE INVENTION

This invention provides methods for the treatment or prevention ofinterstitial cystitis or urethral syndrome in a mammal which compriseadministering to a mammal in need thereof an effective amount ofduloxetine.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

Duloxetine is N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine.It is usually administered as the (+) enantiomer, and as thehydrochloride salt. It was first taught by U.S. Pat. No. 4,956,388,which teaches the synthesis of the compound as well as its high potencyas an uptake inhibitor of both serotonin and norepinephrine. The word"duloxetine" will be used here to refer to any acid addition salt or thefree base of the molecule, as well as to either an enantiomer or theracemate. It is to be understood, however, that the (+) enantiomer ispreferred.

The term "treating" (or "treat") as used herein includes its generallyaccepted meaning which encompasses prohibiting, preventing, restraining,and slowing, stopping, or reversing progression, severity, or aresultant symptom. As such, the methods of this invention encompass boththerapeutic and prophylactic administration.

Duloxetine is a safe drug, and its use in treating or preventinginterstitial cystitis or urethral syndrome, in both adults and children,is a superior treatment for that disorder because of its improvedsafety. The compound is particularly selective, having few if anyphysiological effects besides those on norepinephrine and serotoninprocessing, and therefore is free of side effects and unwantedactivities. Further, it is effective at relatively low doses, asdiscussed below, and may safely and effectively be administered once perday. Thus, difficulties created by the multiple dosing of patients, whoare children and disorganized adults, are completely avoided.

The most preferred dose of duloxetine for the treatment of a givenpatient with any particular disorder will vary, depending on thecharacteristics of the patient, as all clinicians and medical doctorsare aware. Factors such as other diseases from which the patientsuffers, the patient's age and size, and other medications which thepatient may be using will have an effect on the duloxetine dose and willbe taken into account. In general, however, the daily dose of duloxetineis from about 1 to about 80 mg. A more preferred dose range is fromabout 5 to about 40 mg, and another preferred range is from about 5 toabout 20 mg, administered once daily.

Duloxetine is orally available and presently is orally administered, inthe form of a tablet or a capsule full of enteric coated granules. Oraladministration in such forms is preferred in the practice of the presentinvention. However, other routes of administration are also practicaland may be preferred in certain cases. For example, transdermaladministration may be very desirable for patients who are forgetful orpetulant about taking oral medicine. Sustained release formulations,oral or percutaneous, may be prepared, but are not preferred becauseduloxetine is quite effective when administered once daily and there islittle benefit from the additional effort of preparing the sustainedaction product.

In general, the formulation of duloxetine for use in the presentinvention follows the methods used in formulating duloxetine for otherpurposes, and indeed methods usual in pharmaceutical science areappropriate. However, a preferred formulation of duloxetine comprisesenteric pellets, or granules, of which a number are charged in a gelatincapsule.

The preferred duloxetine enteric formulation comprises a) a coreconsisting of duloxetine and a pharmaceutically acceptable excipient; b)an optional separating layer; c) an enteric layer comprisinghydroxypropylmethylcellulose acetate succinate (HPMCAS) and apharmaceutically acceptable excipient; d) an optional finishing layer.The following example demonstrates the preparation of a preferred suchformulation.

EXAMPLE 10 mg Duloxetine Base/Capsule

    ______________________________________                                        Bill of Materials                                                             ______________________________________                                        Beads                                                                           Sucrose - starch nonpareils, 60.28 mg                                         20-25 mesh                                                                    Duloxetine layer                                                              Duloxetine 11.21                                                              Hydroxypropylmethylcellulose 3.74                                             Separating layer                                                              Hydroxypropylmethylcellulose 2.51                                             Sucrose 5.00                                                                  Talc, 500 mesh 10.03                                                          Enteric layer                                                                 HPMCAS, LF grade, Shin-Etsu Chemical 25.05                                    Co., Tokyo, Japan                                                             Triethyl citrate 5.00                                                         Talc, 500 mesh 7.52                                                           Finishing layer                                                               Hydroxypropylmethylcellulose 8.44                                             Titanium dioxide 2.81                                                         Talc Trace                                                                     141.60 mg                                                                  ______________________________________                                    

The duloxetine layer was built up by suspending duloxetine in a 4% w/wsolution of the hydroxypropylmethyl-cellulose in water, and milling thesuspension with a CoBall Mill (Fryma Mashinen AG, Rheinfelden,Switzerland) model MS-12. A fluid bed dryer with a Wurster column wasused to make this product, at a batch size of 1.0 kg. The separatinglayer was added from a 4% w/w solution of thehydroxypropylmethylcellulose in water, in which the sucrose was alsodissolved.

In order to prepare the enteric coating suspension, purified water wascooled to 10° C. and the polysorbate, triethyl citrate and siliconeemulsion were added and dispersed or dissolved. Then the HPMCAS and talcwere added and agitated until homogeneity was obtained, and the HPMCASwas fully neutralized by addition of ammonium hydroxide until solutionof the polymer was complete. To this suspension, acarboxymethylcellulose aqueous solution, 0.5% w/w, was added and blendedthoroughly. The enteric suspension was maintained at 20° C. during thecoating process. The enteric suspension was then added to the partiallycompleted pellets in the Wurster column at a spray rate of about 15ml/min, holding the temperature of the inlet air at about 50° C. Theproduct was dried in the Wurster at 50° C. when the enteric suspensionhad been fully added, and then dried on trays for 3 hours in a dry houseat 60° C. A finishing layer was then applied which consisted of a 4.5%w/w/hydroxypropylmethyl-cellulose solution containing titanium dioxideand propylene glycol as plasticizer. The pellets were completely driedin the fluid bed dryer and then were then filled in size 3 gelatincapsules.

The patient to be benefited by practice of the present invention is apatient having one or more of the disorders discussed in detail below,or who is at a heightened risk of contracting such disorder. Diagnosisof these disorders, or the identification of a patient at risk of one ormore of them, is to be made by a physician or psychiatrist. It ispresently believed that duloxetine's potency in inhibiting the uptake ofserotonin and norepinephrine is the mechanism by which it benefits suchpatients, by alleviating the effects of the disorder from which thepatient suffers, or even eliminating the disorder completely.

It has been determined that the method of the present invention iseffective in treating mammals, particularly middle-aged women,exhibiting symptoms of interstitial cystitis and/or urethral syndrome.In this regard, the clinical and local immune response to the compoundsof the present invention is investigated in an open trail with 10 femaleinterstitial cystitis patients, whose disease is diagnosed according tothe consensus criteria developed in 1987 at a National Institutes ofHealth workshop. To make objective the symptoms and the clinicalresponse of the patients the present inventors scored (scale 0 to 2) thesymptoms of frequency, urgency, nocturia, dysuria and suprapubic pain,as described in U.S. Pat. No. 5,145,859, issued Sep. 8, 1992, the entirecontents of which are herein incorporated by reference. A compound ofthe present invention is administered as a single daily dose determinedby a dose-titration test. Urinary interleukin-2 inhibitory activity(IL-2-IN), a marker of cell-mediated inflammation, is measured using amurine interleukin-2 dependent cell line.

The patients are reviewed for reduction in clinical symptoms. Drugside-effects are minimal. Urinary IL-2-IN activity before therapyconfirms the presence of cell-mediated inflammation: after 4 months oftherapy IL-2-IN activity is normal in most of the patients, regardlessof the severity of symptoms, which indicates that the compounds ofFormula I exerts an immunosuppressive effect. The data suggests that thecompounds of Formula I can be an efficacious, well-tolerated, convenientoral medication for the treatment of interstitial cystitis.

In addition, as more clearly demonstrated below in Example 2, thepresent inventors also observes similar responses in regard to thetreatment of urethral syndrome. As a result, the test data clearlyindicates that the compounds employed in the present invention can beeffective therapeutic agents for the treatment of interstitial cystitisand/or urethral syndrome.

As a result, it has been found that duloxetine is particularlywell-suited for the treatment of interstitial cystitis and/or urethralsyndrome because they not only provide effective relief, are availablefor oral administration, and are relatively inexpensive. It has beendiscovered that patients receiving duloxetine substantially reduce thepathological conditions exhibited by these two painful bladderdisorders, and are able to carry on their daily activities in arelatively normal existence in comparison with their pre-treatmentstate.

The present invention will be further described according to thefollowing non-limiting examples.

Example 1 Materials and Methods

Patients:

The diagnosis of interstitial cystitis is assigned to 10 femalepatients, aged 23 to 51 years, in accordance with the consensus criteriaestablished at the National Institutes of Health workshop oninterstitial cystitis, August, 1987 (Gillenwater, J. Y. and Wein, A. J.:Summary of the National Institute of Arthritis, Diabetes, Digestive andKidney Diseases Workshop on Interstitial Cystitis, National Institutesof Health, Bethesda, Md., Aug. 28-29, 1987, J. Urol., 140:203, 1988),and U.S. Pat. No. 5,145,859:

    ______________________________________                                        Interstitial Cystitis: Criteria for Diagnosis                                     Inclusion Criteria Exclusion Criteria                                     ______________________________________                                        Hunner's Ulcer (if present,                                                                      less than 18 years old                                       automatic inclusion) benign or malignant tumors                                radiation, tuberculous,                                                       bacterial                                                                    Positive Factors (at least 2 or cyclophosphamide cystitis                     required for inclusion): vaginitis                                             duration of symptoms <1 year                                                 suprapubic, pelvic, urethral, gynecologic cancer                              vaginal or perineal pain urethral diverticulum, bladder                        or lower ureteral calculi                                                    glomerulations at cystoscopy active herpes (HSV II)                           after bladder distension waking frequency <5 in 12 hrs.                       (80 cm water pressure × 1 min.) nocturia <2                              neurogenic bladder dysfunction                                               decreased compliance on waking capacity >400 ml,                              cystometrogram absence                                                         of urgency with bladder                                                       filling                                                                       symptoms relieved by                                                          antibiotics, urinary                                                         pain on bladder filling urinary analgesics or                                 relieved by emptying antiseptics                                            ______________________________________                                    

Cystometrics are performed after cessation of other modes of therapy andprior to institution of therapy: all patients had a waking bladdercapacity of less than 350 ml (range 150 ml to 340 ml).

Symptom Evaluation:

The symptom scores (total score range: 0 to 10) form the basis for theevaluation of treatment efficacy. The severity of each symptom isassigned a numerical value, as follows:

    ______________________________________                                        Symptom Severity Survey                                                           Symptom      Description       Score                                      ______________________________________                                        Frequency    voids once every 3 to 5 hours                                                                   0                                                (daytime) voids once every 1 to 2 hours 1                                      voids more than once every hour 2                                            Urgency urge to void equal to actual 0                                         frequency                                                                     urge to void exceeds actual 1                                                 frequency                                                                     constant urge to void 2                                                      Nocturia no nocturia, or 1 void nightly 0                                      nocturia 2 to 4 times nightly 1                                               more than 4 times nightly 2                                                  Dysuria no dysuria 0                                                           intermittent dysuria 1                                                        dysuria with each void 2                                                     Suprapubic pain no pain 0                                                     (abdomino- intermittent pain 1                                                perineal) constant pain 2                                                   ______________________________________                                    

At the time of diagnosis, and before any treatment, any patient whofalls within the parameters of the inclusion of exclusion descriptors ofthe NIH workshop consensus criteria (above) will score at least a "4" onthis survey (frequency<1; urgency<1; nocturia<1; and either dysuria orsuprapubic pain<1).

Urine Collection:

Urine specimens are collected from all patients before and duringtherapy. Voided urine is centrifuged at 1000×g for 10 minutes at 4° C.and the supernatant separated from the sediment. The urine supernatantis subjected to 0.2μ filtration (celluloseacetate) at 4° C. to removeany bacteria and debris, and a 1 ml aliquot is removed for creatininemeasurement (CREATININE II ANALYZER™, Beckman Instruments, Inc., Brea,Calif.). The supernatant is ultrafiltered against 3×volume inphosphate-buffered saline PBS) with 0.1 μg/ml albumin (Sigma, St. Louis,Mo.) using a filtration device (5,000 MW cut off; Amicon, Deavers,Mass.). The concentrated supernatant is dialyzed using 3,500 MW cutofftubing, shell frozen with dry ice, and vacuum lyophilized. The powder isstored at -20° C.

Measurement of IL-2-IN Activity: The bioassay for IL-2-IN is modifiedfrom the method for measuring IL-2 activity described by Gillis andassociates. S. Gillis, et al., "T-Cell Growth Factor: Parameters OfProduction And A Quantitative Microassay For Activity, Journal ofImmunology, 120:2027, (1978). The murine IL-2-dependent cytotoxic T-cellline (CTLL-N) is derived from the CT-6 cell line. J. Kusugami, et al.,"Intestinal Immune Reactivity To Interleukin-2 Differs Among Crohn'sDisease, Ulcerative Colitis And Controls", Gastroenterology, 97:1(1989). The CTLL-Ns are maintained in liquid culture using a 1:1 mixtureof Roswell Park Memorial Institute (RPMI 1640 and Dulbecco's ModifiedEagles Medium (DMEM; 4.5 g/L glucose) media supplemented with 2.9 mg/mlglucose, 9.4 mM HEPES buffer, 1.9 mg/ml glutamine, 289 μg/ml arginine,0.12 M non-essential amino acids, 5×10⁻⁵ M 2-mercaptoethanol, 4.5% fetalbovine serum, 90 units/ml penicillin, 90 μg/ml streptomycin, 22 μg/mlfungizone, 0.45 mg/ml gentamicin and 20 units/ml of human recombinantIL-2.

The CTLL-Ns are washed and suspended at a concentration of 10⁻⁵ /ml inthe culture media. Assays are performed in triplicate, as follows: aserial dilution of the sample aliquot (50 μl), a 1:10 dilution of thehuman recombinant IL-2 standard and 10⁻⁴ CTLL-Ns (100 μl) are placed inmicroliter wells. The microliter plates are incubated in a humidified 6%CO₂ atmosphere at 37° C. for 24 hrs, and the cells are pulsed at the19th hour with 1 μCi/well of methyl-tritiated thymidine (specificactivity 6.7 Ci/mM, New England Nuclear, I. E. Dupont, Boston, Mass.).

The cells are collected onto glass filter paper discs. The discs areplaced in scintillation fluid and thymidine uptake is measured by liquidscintillation spectrophotometry. IL-2 inhibitory activity is calculatedby modified probit analysis.

The proliferation "maximum" is the tritiated thymidine uptake caused bythe amount of exogenous IL-2 activity in the control microliter wells,assessed in quadruplicate for each assay. The proliferation "minimum" isderived from lowest amount of tritiated thymidine uptake caused by theIL-2 inhibitor standard. The probit calculation corrected for minorinterassay variations of thymidine uptake in control wells, andpermitted interassay comparisons of inhibitor activity among the urinesamples. By this treatment of the data, the calculated value of IL-2inhibitory activity in lyophilized urine samples varies less than 10%from assay to assay. IL-2-IN activity is expressed in units/mg urinecreatinine (U/mg u.c.). IL-2-IN activity is less than 0.05 U/mg u.c. inthe urine of healthy adults. J. Fleischmann, et al., Journal ofBiological Regulators and Homeostatic Agents, 4:73, (1990).

Medication Assignments:

All patients are treated initially with a total daily dose of 30 mg,which is administered as a single, extended release tablet.

Patient Monitoring:

Patients are interviewed and blood pressure measured twice monthlyduring the first 2 months of therapy, during the first 2 months after adose escalation, and then once monthly thereafter. The symptom severityscore at each interview is based on the patient's experiences during theprevious 24 hours.

Example 2

In addition to the treatment of patients with interstitial cystitis,patients with the urethral syndrome have been treated with duloxetine,using the titration test and treatment protocol described in U.S. Pat.No. 5,145,859. Similar to the data of Example 1, the positive responseto the compounds of the present invention in this limited study supportsthe hypothesis that the urethral syndrome and interstitial cystitis areboth part of the same disease spectrum, perhaps as variants of reflexsympathetic dystrophy.

The invention has been described with reference to the preferredembodiment. Obviously, modifications and alterations will occur toothers upon a reading and understanding of this specification. It isintended to include all such modifications and alterations insofar asthey come within the scope of the appended claims or the equivalentsthereof.

While it is possible to administer a compound employed in the methods ofthis invention directly without any formulation, the compounds areusually administered in the form of pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and at least oneactive ingredient. These compositions can be administered by a varietyof routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Many of the compoundsemployed in the methods of this invention are effective as bothinjectable and oral compositions. Such compositions are prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. See. e.g, REMINGTON'S PHARMACEUTICAL SCIENCES, (16thed. 1980).

In making the compositions employed in the present invention the activeingredient is usually mixed with an excipient, diluted by an excipientor enclosed within such a carrier which can be in the form of a capsule,sachet, paper or other container. When the excipient serves as adiluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing forexample up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, it may be necessary to mill the activecompound to provide the appropriate particle size prior to combiningwith the other ingredients. If the active compound is substantiallyinsoluble, it ordinarily is milled to a particle size of less than 200mesh. If the active compound is substantially water soluble, theparticle size is normally adjusted by milling to provide a substantiallyuniform distribution in the formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxybenzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions are preferably formulated in a unit dosage form, eachdosage containing from about 0.05 to about 100 mg, more usually about1.0 to about 30 mg, of the active ingredient. The term "unit dosageform" refers to physically discrete units suitable as unitary dosagesfor human subjects and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient.

The active compounds are generally effective over a wide dosage range.For examples, dosages per day normally fall within the range of about0.01 to about 30 mg/kg of body weight. In the treatment of adult humans,the range of about 0.1 to about 15 mg/kg/day, in single or divided dose,is especially preferred. However, it will be understood that the amountof the compound actually administered will be determined by a physician,in the light of the relevant circumstances, including the condition tobe treated, the chosen route of administration, the actual compound orcompounds administered, the age, weight, and response of the individualpatient, and the severity of the patient's symptoms, and therefore theabove dosage ranges are not intended to limit the scope of the inventionin any way. In some instances dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smallerdoses for administration throughout the day. In addition to the enterictablet formulation described, supra, the present invention also employsmethods of treating or preventing interstitial cystitis or urethralsyndrome employing duloxetine in a number of formulations. Examples ofsuch formulations follow.

    ______________________________________                                        Formulation Preparation 1                                                       Hard gelatin capsules containing the following ingredients                    are prepared:                                                                                   Quantity                                                    Ingredient (mg/capsule)                                                     ______________________________________                                        Active Ingredient(s)                                                                          30.0                                                            Starch 305.0                                                                  Magnesium stearate 5.0                                                      ______________________________________                                         The above ingredients are mixed and filled into hard gelatin capsules in      340 mg quantities.                                                       

    ______________________________________                                        Formulation Preparation 2                                                       A tablet formula is prepared using the ingredients below                                          Quantity                                                  Ingredient (mg/tablet)                                                      ______________________________________                                        Active Ingredient(s)                                                                            25.0                                                          Cellulose, microcrystalline 200.0                                             Colloidal silicon dioxide 10.0                                                Stearic acid 5.0                                                            ______________________________________                                         The components are blended and compressed to form tablets, each weighing      240 mg.                                                                  

    ______________________________________                                        Formulation Preparation 3                                                       A dry powder inhaler formulation is prepared containing the                   following components                                                                Ingredient   Weight %                                                 ______________________________________                                        Active Ingredient(s)                                                                           5                                                              Lactose 95                                                                  ______________________________________                                    

The active mixture is mixed with the lactose and the mixture is added toa dry powder inhaling appliance.

    ______________________________________                                        Formulation Preparation 4                                                       Tablets, each containing 30 mg of active ingredient, are                      prepared as follows                                                                                    Quantity                                             Ingredient (mg/tablet)                                                      ______________________________________                                        Active Ingredient(s)    30.0 mg                                                 Starch 45.0 mg                                                                Microcrystalline cellulose 35.0 mg                                            Polyvinylpyrrolidone 4.0 mg                                                   (as 10% solution in water)                                                    Sodium carboxymethyl starch 4.5 mg                                            Magnesium stearate 0.5 mg                                                     Talc 1.0 mg                                                                   Total 120 mg                                                                ______________________________________                                    

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50-60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

    ______________________________________                                        Formulation Preparation 5                                                       Capsules, each containing 40 mg of medicament are made as                     follows                                                                                               Quantity                                              Ingredient (mg/capsule)                                                     ______________________________________                                        Active Ingredient(s)  40.0 mg                                                   Starch 109.0 mg                                                               Magnesium stearate 1.0 mg                                                     Total 150.0 mg                                                              ______________________________________                                    

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 20 mesh U.S. sieve, and filled into hardgelatin capsules in 150 mg quantities.

    ______________________________________                                        Formulation Preparation 6                                                       Suppositories, each containing 25 mg of active ingredient are                 made as follows                                                                   Ingredient            Amount                                            ______________________________________                                        Active Ingredient(s)    25 mg                                                   Saturated fatty acid glycerides to 2,000 mg                                 ______________________________________                                    

The active ingredient(s) is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool

    ______________________________________                                        Formulation Preparation 7                                                       Suspensions, each containing 50 mg of medicament per 5.0                      ml dose are made as follows                                                      Ingredient              Amount                                           ______________________________________                                        Active Ingredient(s)     50.0   mg                                              Xanthan gum 4.0 mg                                                            Sodium carboxymethyl cellulose (11%) 50.0 mg                                  Microcrystalline cellulose (89%)                                              Sucrose 1.75 g                                                                Sodium benzoate 10.0 mg                                                       Flavor and Color q.v.                                                         Purified water to 5.0 ml                                                    ______________________________________                                    

The medicament, sucrose and xanthan gum are blended, passed through aNo. 10 mesh U.S. sieve, and then mixed with a previously made solutionof the microcrystalline cellulose and sodium carboxymethyl cellulose inwater. The sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added toproduce the required volume.

    ______________________________________                                        Formulation Preparation 8                                                       Capsules, each containing 15 mg of medicament, are made as                    follows                                                                                               Quantity                                              Ingredient (mg/capsule)                                                     ______________________________________                                        Active Ingredient(s)  15.0 mg                                                   Starch 407.0 mg                                                               Magnesium stearate 3.0 mg                                                     Total 425.0 mg                                                              ______________________________________                                         The active ingredient(s), cellulose, starch, and magnesium stearate are       blended, passed through a No. 20 mesh U.S. sieve, and filled into hard        gelatin capsules in 425 mg quantities.                                   

    ______________________________________                                        Formulation Preparation 9                                                       An intravenous formulation may be prepared as follows                               Ingredient        Quantity                                            ______________________________________                                        Active Ingredient(s)  250.0  mg                                                 Isotonic saline 1000 ml                                                     ______________________________________                                    

    ______________________________________                                        Formulation Preparation 10                                                      A topical formulation may be prepared as follows                                    Ingredient         Quantity                                           ______________________________________                                        Active Ingredient(s)   1-10 g                                                   Emulsifying Wax 30 g                                                          Liquid Paraffin 20 g                                                          White Soft Paraffin to 100 g                                                ______________________________________                                    

The white soft paraffin is heated until molten. The liquid paraffin andemulsifying wax are incorporated and stirred until dissolved. The activeingredient is added and stirring is continued until dispersed. Themixture is then cooled until solid.

    ______________________________________                                        Formulation Preparation 11                                                      Sublingual or buccal tablets, each containing 10 mg of active                 ingredient, may be prepared as follows                                                                 Quantity                                             Ingredient Per Tablet                                                       ______________________________________                                        Active Ingredient(s)   10.0 mg                                                  Glycerol 210.5 mg                                                             Water 143.0 mg                                                                Sodium Citrate 4.5 mg                                                         Polyvinyl Alcohol 26.5 mg                                                     Polyvinylpyrrolidone 15.5 mg                                                  Total 410.0 mg                                                              ______________________________________                                    

The glycerol, water, sodium citrate, polyvinyl alcohol, andpolyvinylpyrrolidone are admixed together by continuous string andmaintaining the temperature at about 90° C. When the polymers have goneinto solution, the solution is cooled to about 50-55° C. and themedicament is slowly admixed. The homogenous mixture is poured intoforms made of an inert material to produce a drug-containing diffusionmatrix having a thickness of about 2-4 mm. This diffusion matrix is thencut to form individual tablets having the appropriate size.

Another preferred formulation employed in the methods of the presentinvention employs transdermal delivery devices ("patches"). Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. See. e.g,U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated byreference. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Frequently, it will be desirable or necessary to introduce thepharmaceutical composition to the brain, either directly or indirectly.Direct techniques usually involve placement of a drug delivery catheterinto the host's ventricular system to bypass the blood-brain barrier.One such implantable delivery system, used for the transport ofbiological factors to specific anatomical regions of the body, isdescribed in U.S. Pat. No. 5,011,472, issued Apr. 30, 1991, which isherein incorporated by reference.

Indirect techniques, which are generally preferred, usually involveformulating the compositions to provide for drug latentiation by theconversion of hydrophilic drugs into lipid-soluble drugs or prodrugs.Latentiation is generally achieved through blocking of the hydroxy,carbonyl, sulfate, and primary amine groups present on the drag torender the drug more lipid soluble and amenable to transportation acrossthe blood-brain barer. Alternatively, the delivery of hydrophilic drugsmay be enhanced by intra-arterial infusion of hypertonic solutions whichcan transiently open the blood-brain barrier.

We claim:
 1. A method for the treatment or prevention of interstitialcystitis or urethral syndrome in a mammal which comprise administeringto a mammal in need thereof an effective amount of duloxetine.
 2. Amethod as claimed in claim 1 wherein the mammal is administered between30 and 150 mg of duloxetine per day.
 3. A method as claimed in claim 2wherein the duloxetine is administered as an enteric tablet.